The trouble with TEFs.
Comments on Van den Berg, et al. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106:775-792 (1998)
Animals↗
Biomedical subjects
R A Neal
Publications and source records attributed to R A Neal.
The sensitivity of Leishmania species to aminosidine.
The aminoglycoside, aminosidine exhibited ED50S of between 1 and 5 microM against the amastigotes of Leishmania major and Leishmania tropica in mouse peritoneal macrophages whereas other strains causing New World cutaneous leishmaniasis such as Leishmania braziliensis were more refractory. Aminosidine was also active against all but one of the Leishmania donovani strains tested and when combined with sodium stibogluconate, the drug showed marked potentiation against the amastigotes of L. donovani in vitro and an additive effect in experimentally infected BALB/c mice.
Animals↗
The activity of platinum, iridium and rhodium drug complexes against Leishmania donovani.
The activities of twenty seven Platinum, Rhodium and Iridium drug complexes were determined against Leishmania donovani amastigotes in mouse peritoneal macrophages in vitro. Eight compounds showed antileishmanial activity of which only three, Rh(III)-mepacrine, Ir(III) pyrrolidine dithiocarbamate and Ir(III) diethyl dithiocarbamate had ED50 values of less than 1 microM. The two Iridium complexes produced, respectively, a 50% and 39% suppression of L. donovani amastigotes in the liver of BALB/c mice following the subcutaneous administration of 200 mg/kg for 5 consecutive days. Ultrastructural studies suggest that the amastigote kinetoplast-mitochondrion complex is the primary site of action of the Ir and Rh complexes.
Animals↗
Hydrazide antidepressants possess novel antileishmanial activity in vitro and in vivo.
The hydrazide monoamine oxidase inhibitor antidepressants possess a novel antiparasitic action against visceral and cutaneous strains of Leishmania. In vitro, phenelzine was the most active compound tested, while in vivo, nialamide was more potent, and was also effective when applied topically to cutaneous lesions. Despite the coincidence of tricyclic antidepressants also possessing antileishmanial activity, the evidence suggests that the antiparasitic action of the hydrazides is unrelated to either monoamine oxidase inhibition or CNS effects.
Animals↗
Antileishmanial effects of clofazimine and other antimycobacterial agents.
In the search for more effective alternatives to the presently-used antileishmanial drugs, the activity of the major groups of antimycobacterial compounds has been examined, both in vitro and in animal models of infection. In vitro, clofazimine was the most active compound tested, with a mean ED50 of 2.3 mg l-1 against Leishmania mexicana amazonensis, 1.4 mg l-1 against L. donovani and 0.5 mg l-1 against L. major. Other active compounds were the thiosemicarbazone, thiambutosine, and salinazid, a derivative of isoniazid. Isoniazid itself was inactive, and rifampicin only partially active. In vivo, only clofazimine displayed significant activity, and it was most effective against the cutaneous infections. It is concluded that antimycobacterial activity is in general a poor predictor of antileishmanial potency.
Administration, Topical↗
Antileishmanial effect of free and encapsulated sinefungin against Leishmania donovani infections in BALB/c mice.
Sinefungin, a C-nucleoside antibiotic, displays a high antiparasitic action. The effect of free and microencapsulated sinefungin was compared on BALB/c mice infected with Leishmania donovani; the encapsulated form proved more effective by one order of magnitude.
Adenosine↗
Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro.
A comparative study showed that 5 laboratory strains of Trypanosoma cruzi could be divided into a non-responsive group (Sonya clone and Colombiana) and a responsive group (Tulahuén, Y and Peru), based on long-term treatment of mouse infections with nifurtimox and benznidazole. In vitro sensitivity of epimastigotes and blood-stream trypomastigotes in macrophage cultures did not distinguish the strains, nor did the rate of development of nifurtimox resistance by epimastigote cultures. 7 novel anti-T. cruzi compounds also behaved similarly with respect to the 2 groups. A small decrease in sensitivity was observed in vitro by non-responsive strains of T. cruzi after re-isolation from treated mice. It is postulated that there could be an immunological component involved in successful treatment of T. cruzi infection.
Animals↗
Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines.
The classical anti-microbial antifolates trimethoprim, pyrimethamine, and cycloguanil are poor inhibitors of purified dihydrofolate reductase (DHFR) from Leishmania major. They show no selectivity for Leishmania DHFR relative to the human enzyme, and it is not surprising that they are ineffectual as anti-leishmanial agents. Several 5-(substituted-benzyl)-2,4-diaminopyrimidines have been screened as inhibitors for purified L. major and human DHFRs. These compounds inhibit Leishmania DHFR with I50 values ranging from 0.2 to 11 microM, and show about 5 to greater than 100-fold greater selectivity for the parasite DHFR than the human enzyme. These pyrimidine analogs are more potent inhibitors of Leishmania promastigote and amastigote growth than the classical anti-microbial antifolates, and serve as lead compounds for the development of new selective antileishmanial agents.
Animals↗
The activity of nitrofurazone and furazolidone against Leishmania donovani, L. major and L. enriettii in vitro and in vivo.
Furazolidone and nitrofurazone showed in vitro activity against amastigotes of Leishmania donovani, L. enriettii and L. major in macrophages, at concentrations which were also toxic to the macrophages. A low grade of activity was observed against L. donovani infections in BALB/c mice by furazolidone but not with nitrofurazone. Nitrofurazone, in two concentrations, was not active when applied to the lesions of cutaneous leishmaniasis due to L. enriettii (guinea-pig infection) or L. major strain P (BALB/c mouse infection). After systemic administration to BALB/c mice infected with L. major strain JISH 252 clone 1, low-grade activity was observed at the highest level tested.
Animals↗
In vitro anti-Leishmanial activity of compounds in current clinical use for unrelated diseases.
Drugs in current clinical use were tested for anti-Leishmania activity using an in vitro infected macrophage assay. Out of almost 400 compounds tested, over 100 were active. The most active compounds showed ED50 values below 1 microM concentration. It is concluded that the active compounds should receive testing in the in vivo system. In addition they will act as lead compounds for further synthetic programmes.
Animals↗
The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani.
Several alkyl phosphorylcholines and related derivatives were tested against Leishmania donovani amastigotes in mouse peritoneal macrophages in vitro and ED50 values were determined in the range of 1-12 microM. The three alkyl phosphorylcholines tested against L. donovani in BALB/c mice were active, an ED50 of 12.8 mg/kg/day X 5 was ascertained for one compound, but an alkyl phosphorylethanolamine was inactive.
Alkylation↗
Oxidative metabolism of carbon disulfide by isolated rat hepatocytes and microsomes.
The oxidative metabolism of carbon disulfide (CS2) was investigated in isolated rat hepatocytes and liver microsomes. In microsomes, CS2 metabolism was increased by phenobarbital pretreatment of the rats and decreased with pretreatment of the rats with cobaltous chloride. In both microsomes and hepatocytes, CS2 metabolism was inhibited by SKF-525A. Carbon dioxide (CO2) was the major volatile metabolite of CS2 in hepatocytes, and carbonyl sulfide (COS) was the major volatile metabolite in microsomal incubations. Addition of cytosol to microsomal incubations shifted the predominant volatile metabolite from COS to CO2 but did not change total volatile metabolite formation. Acetazolamide, a carbonic anhydrase inhibitor, significantly decreased COS metabolism but not CS2 metabolism in isolated hepatocytes or microsomes fortified with dialyzed cytosol. When [18O]H2O was included in incubations of microsomes and CS2, a substantial portion of the resulting COS was [18O] enriched, indicating that the oxygen atom was derived from water. These data are consistent with the hypothesis that CS2 is oxidized predominantly by the cytochrome P-450 containing monooxygenase system, and the product of this reaction is an unstable intermediate which reacts with water to form monothiocarbonate and reactive sulfur species. Monothiocarbonate is the hydrated form of COS. In intact hepatocytes, it is metabolized predominantly to CO2 and hydrogen sulfide. Unmetabolized monothiocarbonate can be dehydrated to COS. The majority of the reactive sulfur species and hydrogen sulfide are oxidized to nonvolatile sulfur compounds, including sulfate, but by different mechanisms.
Acetazolamide↗
Failure of meglumine antimoniate to cure cutaneous lesions due to Leishmania major in Algeria.
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Adolescent↗
Immunization of marmosets with Trypanosoma cruzi cell surface glycoprotein (GP90).
Marmosets (Callithrix jacchus) have been immunized with a vaccine comprising a Trypanosoma cruzi 90K cell surface glycoprotein and the adjuvant saponin; a combination previously shown to be protective in mice. Immunization was by two s.c. injections one month apart and non-lethal challenge of homologous Y strain T. cruzi was given one month after the booster immunization. No anti-T. cruzi antibodies were detected after the first immunization but high levels developed after boosting. Immunization caused a significant decrease in the levels of acute phase blood parasitaemia, however, both immunized and control animals remained xenodiagnosis positive 60 weeks after infection. No ECG aberrations, histopathological lesions or anti-tissue antibodies were detected in infected marmosets.
Adjuvants, Immunologic↗
The effect of allopurinol ribonucleoside and formycin B on Trypanosoma cruzi infections in mice.
The anti-Trypanosoma cruzi effect of allopurinol ribonucleoside and formycin B was examined against infections of the sensitive Y and Peru strains in inbred mice, strain DBA/1. Allopurinol ribonucleoside given in the drinking water at doses calculated to be 239, 511 and 929 mg/kg/day for 28 days, prevented the death of the mice but did not eradicate the infection. Formycin B given orally at 100 and 10 mg/kg/day X 5 days, showed a similar effect.
Allopurinol↗